Infections with human acquired immunodeficiency virus (HIV), a kind of retrovirus, have become one of gravest social problems in recent years. However, there are only three antiviral agents clinically available in the treatment of HIV infections at present. They all belong to nucleoside compounds, that is, 3'-azide-3'-deoxythymidine (AZT, Zidovudine), 2',3'-dideoxyinosine (ddI, Didanosine) and 2',3'-dideoxycytidine (ddC, Zalcitabine).
Although these existing nucleoside compounds can inhibit HIV reverse transcriptase, often through the inhibition of their triphosphorylation, and are potent antiviral agents, they have problems of various side effects and are highly toxic. For example, it has been reported that AZT may cause severe anemia or leukopenia due to suppression of bone marrow and ddI may cause peripheral nervus disorders or acute pancreatitis.
Further, a long-term treatment with these nucleoside derivatives can result in the appearance of drug-resistant mutant, which is a serious problem among practitioners.
Lately, there have been developed compounds that inhibit HIV reverse transcriptase through a novel mechanism, which are called "allosteric inhibitors" because they exert their effect by binding to "allosteric positions", i.e., those other than the substrate-binding-site, of the enzyme (European Patent Publication Nos. 384522, 429987, 462800, and 420763). These compounds are potent HIV inhibitors with less cytotoxicity compared to nucleoside compounds.
As the HIV infection is becoming more and more serious, it is strongly demanded to develop effective and low-toxic antiviral agents.